Hy's Law Research Articles

Hepatobiliary abnormalities in patients with metastatic cancer treated with lapatinib

1043 Background: Lapatinib (LAP), a dual tyrosine kinase inhibitor (TKI), is effective in the treatment of HER-2-positive metastatic breast cancer. Liver toxicity has been reported as a side effect of several TKIs. We analyzed the liver safety of LAP using available data from 16 metastatic cancer trials. Methods: LAP (as monotherapy or in combination) was administered to 2,968 patients (pts) in metastatic cancer trials. Liver function tests were prospectively evaluated. We defined liver toxicity events as either NCI CTCAE grade (Gr) 3 or 4 alanine and aspartate aminotransaminases (ALT/AST) or meeting Hy's Law criteria (liver injury with jaundice). Results: Overall Gr 3 and 4 ALT/AST events were seen in 45/2,968 (1.5%) and 2/2,968 (0.07%) pts, respectively. Of LAP monotherapy pts, Gr 3 and 4 ALT/AST was seen in 13/1,470 (0.9%) and 1/1,470 (0.07%), respectively. Of LAP + monoclonal antibody (mAb) pts (trastuzumab or bevacizumab), Gr 3 and 4 ALT/AST was seen in 2/199 (1.0%) and 1/199 (0.5%), respectively. Ten of 645 pts (1.6%) treated with LAP + chemotherapy (capecitabine or paclitaxel) had Gr 3 ALT/AST. Twenty of 654 pts (3%) treated with LAP + letrozole had Gr 3 ALT/AST. Among 2,968 pts, Hy's law toxicity occurred in 8 (0.3%) pts: 2/1,470 (0.14%) pts treated with LAP alone, 1/199 (0.5%) pts treated with LAP + mAb, 4/645 (0.6%) pts treated with LAP + chemotherapy, and 1/654 (0.2%) pts treated with LAP + letrozole. Alternative causes of liver toxicity such as metastatic liver disease, infectious hepatitis, and heart failure will be reported at the meeting. Conclusions: Review of data from 16 clinical trials in metastatic cancer revealed low levels of liver toxicity for LAP. Oncologists should be vigilant for this rare side effect of LAP. A proposed monitoring algorithm of symptom assessment and frequency of hepatobiliary laboratory monitoring will be shown. [Table: see text]

Drug-induced liver injury in 2007

To summarize the pertinent literature on the causes, epidemiology, prevalence, clinical features, evaluation and mechanisms of drug-induced liver injury reported during 2007. Although the frequency of drug-induced liver injury remains low, new data from the Centers for Disease Control and Prevention confirm that of the approximately 1600 new acute liver failure cases annually, acetaminophen hepatotoxicity accounts for 41%; among children with acute liver failure, acetaminophen was the second most common cause. Antimicrobials lead the list of non-acetaminophen causes of drug-induced liver injury. In Asia, herbal compounds are the most common causes of the condition. Pravastatin was shown to be safe in patients with nonalcoholic fatty liver disease or chronic hepatitis C. The US Food and Drug Administration issued a draft guidance document on the premarketing clinical evaluation and stopping rules of drug-induced liver injury signals, including Hy's Law cases in clinical trials. The year 2007 brought with it several reminders of the importance of drug-induced liver injury in the clinical trial as well as the clinical practice setting. There is additional evidence that statin drugs may be used safely in patients with chronic liver disease. Comments received by the US Food and Drug Administration to finalize their guidance document are eagerly awaited.

Drug-induced liver disease

To summarize the pertinent case reports, case series and clinical studies that described clinical, histological, epidemiological and mechanistic features of drug-induced liver disease in 2005. Acetaminophen, highly active antiretroviral therapy and drugs for tuberculosis retained their preeminent position as the most commonly reported agents causing drug-induced liver disease, with acetaminophen continuing to be the leading cause of acute liver failure in the USA. While the frequency of drug-induced liver disease remains low, a large case-series of acute drug-induced liver disease from Spain and Sweden supported the observation that acute hepatocellular jaundice from a drug is associated with death or the need for transplant in at least 10% (known as Hy's Law). With respect to using potentially hepatotoxic medications in patients with underlying liver disease, statins and second-generation thiazolidinediones were shown to be safe when used in patients with elevated baseline alanine aminotransferase or aspartate aminotransferase levels. Drug-induced liver disease remains an important cause of acute liver failure, and research efforts by the National Institutes of Health and others are underway to better determine the risk factors and other host susceptibilities that will allow for the safer use of drugs in the future.

How can ‘Hy's law’ help the clinician?

How can ‘Hy's law’ help the clinician?

Hy's law: predicting serious hepatotoxicity

Hy's law: predicting serious hepatotoxicity

‘Hy's law,’ the ‘Rezulin Rule,’ and other predictors of severe drug‐induced hepatotoxicity: putting risk‐benefit into perspective

Pharmacoepidemiology and Drug SafetyVolume 15, Issue 4 p. 221-229 Perspective ‘Hy's law,’ the ‘Rezulin Rule,’ and other predictors of severe drug-induced hepatotoxicity: putting risk-benefit into perspective† James H. Lewis MD, FACP, FACG, Corresponding Author James H. Lewis MD, FACP, FACG [email protected] Division of Gastroenterology, Georgetown University Medical Center, Washington, District of Columbia, USAProfessor of Medicine, Director of Hepatology, Georgetown University Medical Center, Rm 2408 Main Hospital, 3800 Reservoir Road, NW, Washington, District of Columbia 20007, USA.Search for more papers by this author James H. Lewis MD, FACP, FACG, Corresponding Author James H. Lewis MD, FACP, FACG [email protected] Division of Gastroenterology, Georgetown University Medical Center, Washington, District of Columbia, USAProfessor of Medicine, Director of Hepatology, Georgetown University Medical Center, Rm 2408 Main Hospital, 3800 Reservoir Road, NW, Washington, District of Columbia 20007, USA.Search for more papers by this author First published: 30 January 2006 https://doi.org/10.1002/pds.1209Citations: 61 † No conflict of interest was declared. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume15, Issue4April 2006Pages 221-229 RelatedInformation

Hy's law.

Hy's law.